Note: Descriptions are shown in the official language in which they were submitted.
s 2 1 946~4
-
Le A 30 528-PCT
~L~ P~JT~ ;J ~
~ R ~
Pvrido~3.2~ 3.11benzoxazine derivatives
The invention relates to new pyrido[3,2, 1-i,j][3, I]benzoxazine derivatives, toprocesses for their preparation, and to antibacterial compositions comprising them.
It has already been disclosed that pyridobenzoxazinecarboxylic acids have an
antibacterial activity. Examples can be found in EP-O 373 531.
There have now been found compounds of the general formula (I)
x1~ CoOR4
R~J< R3 ( I ) .
R2 ~ R3
in which
R1 represents hydrogen or C~-C4-alkyl which is optionally substituted by
hydroxyl or halogen,
R2 independently of Rl represents hydrogen or methyl,
R3 represents hydrogen or Cl-C4-alkyl,
R3 independently of R3 represents hydrogen or methyl,
R4 represents hydrogen, alkyl having I to 4 carbon atoms which is optionally
substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or
represents (S-methyl-2-oxo-1,3-dioxol-4-yl)-methyl,
; ' ' ''' ''''' 2 i 9 '' ' ' ;'''' ' ''; '
Xl represents hydrogen or halogen,
Z represents radicals of the structures
~' N_ R9 ~CN-- 5~;~CN--
in which
S R7 represents hydrogen, hydroxyl, -NRI~Rll, hydroxymethyl, -CH2-NRl~RIl,
carboxyl, methoxycarbonyl or ethoxycarbonyl,
where
Rl~ represents hydrogen, Cl-C3-alkyl which is optionally substituted by
hydroxyl, or represents alkoxycarbonyl having 1 to 4 C atoms in the
10alkoxy moiety, or Cl-C3-acyl,
Rl I represents hydrogen or methyl,
R8 represents hydrogen, straight-chain or branched Cl-C3-alkyl or cyclopropyl,
R9 represents hydrogen or methyl,
R6 represents hydrogen or methyl,
15 R5 represents hydrogen, methyl or radicals of the structures -CH=CH-CO2Rs,
-CH2-CH2-Co2R5,-CH2-CO-CH3,-CH2-CH2-CN,
R5 represents methyl or ethyl, and
B represents -CH2-, 0 or a direct bond.
2 i 94694
The compounds of the formula (I) can exist in the form of racemates or
enantiomerically pure compounds, in the form of their pharm~ce~ltically utilizable
hydrates and acid addition salts, and in the form of their alkali metal salts, alkaline
earth metal salts, silver salts and guanidinium salts
S The compounds of the formula (I) are obtained when compounds of the formula (II)
o
X1~3,CooR4
X2~R3 ( Il ),
R2 ~ R3
in which
Rl, R2, R3, R3, R4 and Xl have the abovementioned meaning and
X2 represents halogen, in particular fluorine or chlorine,
10 are reacted with compounds of the formula (III)
Z-H (III),
in which
Z has the abovementioned meaning,
if appropriate in the presence of acid scavengers
15 Compared with known representatives of this structural type, the compounds
according to the invention have a more powerful antibacterial action, in particular in
the Gram-positive sector. They are therefore suitable as active compounds for human
and veterinary medicine, veterinary medicine also including the treatment of fish for
the therapy or the prevention of bacterial infections.
20 Preferred compounds of the formula (I) are those in which
2 1 946q4
Rl represents hydrogen or Cl-C3-alkyl which is optionally substituted by
hydroxyl,
R2 independently of Rl represents hydrogen or methyl,
R3 represellt~. hydrogen, methyl or ethyl,
S R3 independently of R3 represents hydrogen or methyl,
R4 represents hydrogen, alkyl having 1 to 4 carbon atoms which is optionally
substituted by hydroxyl, methoxy, amino, methylamino or dimethylamino, or
represents (S-methyl-2-oxo-1,3-dioxol-4-yl)methyl,
Xl represents hydrogen, fluorine or chlorine,
10 Z represents radicals of the structures
R7 R7
R8~N-- , R9~ 6~8
in which
R7 represents hydrogen, hydroxyl, -NRI~Rll, hydroxymethyl or -CH2-NRI~Rll,
where
Rl~ represents hydrogen, Cl-C2-alkyl which is optionally substituted by
hydroxyl, or represents alkoxycarbonyl having 1 to 4 C atoms in the
alkoxy moiety, or Cl-C3-acyl,
Rll represents hydrogen or methyl,
R8 represents hydrogen, straight-chain or branched Cl-C3-alkyl or cyclopropyl,
20 R9 represents hydrogen or methyl,
2 1 94694
R5 represents hydrogen or methyl,
R6 represents hydrogen, and
B represents -CH2-, 0 or a direct bond,
and their pharmaceutically utilizable hydrates and acid addition salts, as well as their
5 alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.
Particularly plefelled compounds of the formula (I) are those in which
Rl represents hydrogen or methyl,
R2 hydrogen,
R3 represents methyl or ethyl,
10 R3 represents hydrogen or methyl,
R4 represents hydrogen, methyl or ethyl,
xl represents fluorine,
Z represents radicals of the structures
R7 R7 R
R ~CN-- , Rg~ N ~C
15 in which
R7 represents hydrogen, hydroxyl, -NRI~RIl, hydroxymethyl or-CH2-NRI~RIl,
where
2 1 94694
Rl~ lepresents hydrogen, methyl, alkoxycarbonyl having 1 to 4 C atoms in
the alkoxy moiety or C1-C3-acyl,
Rll represents hydrogen or methyl,
Rg represents hydrogen, straight-chain or branched Cl-C3-alkyl or cyclopropyl,
S R6 represents hydrogen,
R9 represents hydrogen or methyl,
Rs represents hydrogen or methyl, and
B represents -CH2-, 0 or a direct bond,
and their ph~ ceutically utilizable hydrates and acid addition salts, as well as their
10 alkali metal salts, alkaline earth metal salts, silver salts and guanidinium salts.
21 946Y4
The following compounds of the formula (I) may be mentioned specifically:
X 'T ~CooR4
~< . ( 1)~
~ R3
R3~ R3 R4 z X
H Me H I H3 F
~N~
~ N--
H Me H CH3 F
~N~ ,
~0~
H Me H I H3 F
<~XN--
H Me Et H F
~CN--
21 946~4
-
Continuation:
X~ 3"COOR4
~,1< ( I ).
~ R3
R3~ R3 R4 z X
H Et H H F
~N~
~ N--
S Me Me H H F
~N--
Me Me H H F
~N~
~0~
CH20H Me H H F
~N~
~L N--
H H H ~ F
~N--
NH2
2 1 94694
Continuation:
X~,CooR4
~< ( 1).
~ R3
R3~ R3 R4 z X
H H ethyl ,~ F
~N--
NH2
S H H H Me~ F
~N--
NH2
H H H ~ ~ F
~N--
NH2
CH3 H ethyl ,~ ~ F
~N--
NH2
H H-CH2-CH2-NH2 ~ F
~N--
NH2
;
2 1 946~4
Continuation:
X~ CoOR4
~ ( 1),
~ R3
R3~ R3 R4 z X
H H-CH2-CH2-OcH3 ~ F
~N--
NH2
S CH3 H H Me F
~N--
NH2
CH3 CH3 H ~ F
~N--
NH2
H CH3 ethyl ~ F
~N--
NH2
H CH3-CH2-CH2-NH2 ~ F
~N--
NH2
- 10 -
21 94~4
-
Continuation:
z~ ~ oR4 (1),
R3~ R3 R4 z X
H CH3-CH2-CH2-OCH3 ~\ F
~N--
NH2
H Hethyl ~ F
~N--
NH2
CH3 H H ~ F
~N--
NH2
CH3 CH3 H ~ F
~N--
NH2
21 946~~
. .
X~ ,CoOR4
Z~N R3 (1),
~oJ<R3,
R3~ R3 R4 z X
H Me H NH2 F
J~N--
Me
H Me H NH2 F
~J ,N--
H Me H CH2NH2 F
W ~N--
H Et H NHCH3 F
W ,N--
Me Me H NH2 F
W ,N--
- 12 -
21946~4
Continuation:
x ~,CooR4
O J<R3
R3~ R3 R4 z X
CH20H Me H NH2 F
~CN--
S H Me H NH2 F
~J--ZN
H Me H NHCH3 F
[~CN--
H Me H NHC2H5
~N--
H Me H N(C H3)2 F
~N--
13 -
. 2194694
-
Continuation:
x ~,CooR4
Z~N R3 (1),
~oJ<R3.
R3~ R3 R4 z X
H Me H CH2NH2 F
~ ,N--
H Me H CH2NHCH3 F
~ ,N--
H Me H NH2 F
H3C~
~ ,N--
H Me H NH2 F
~ '
~,N--
CH3
H Me H NH2 F
~N--
CH3
- 14
21 946~
Continuation:
X ~T~,CooR4
~oJ<R3~ ( I ),
R3~ R3 R4 z X
H Me H NHCO2Et F
b~N--
H Me H ~ F
H Me H CH20H F
~N--
H Me H CH2NHCO2Et F
~N--
Me Me H NHCH3 F
~CN--
2194b94
Continuation:
X~CoOR4
~< ( 1).
~ R3
R3~ R3 R4 z X
Me Me H CH2NH2 F
~N--
CH20H Me H NH2 F
[~N--
CH20H Me H NHC H3 F
~CN--
CH20H Me H CH2NH2 F
[~N--
H Et H NH2 F
~J ~N--
- 16 -
2 1 94694
Continuation:
X~ CooR4
~oJ<R3. ( I ).
R3~ R3 R4 z X
H Et H NHCH3 F
~N--
S H Me Et NH2 F
{~CN--
H Me Et NHCH3 F
~CN--
2 1 946~
'
If, for example, 9,10-difluoro-3-methyl-7-oxo-lH, 3H, 7H-pyrido[1,2,3-d,e]-
[3,1]benzoxazine-6-carboxylic acid and 2,8-diazabicyclo[4.3.0]nonane are used for
the preparation of compounds of the formula (I), the course of the reaction can be
represented by the following equation:
~ ' ~ ~1
The compounds of the formula (II) which are used as starting compounds are knownor can be prepared by known processes. If appropliate, they can be employed in the
form of the racçm~tes, enantiomers or pure diastereomers.
Examples which may be mentioned are:
9,10-difluoro-3-methyl-7-oxo-lH,3H,7H-pyrido-[3,2,1-i,j][3,1]benzoxazine-
6-carboxylic acid
9,10-difluoro-3-ethyl-7-oxo-lX3X7H-pyrido-[3,2,1-i,j][3,1]b~ n7.ox~7ine-6-carboxylic
acld
9,10-chloro-3-methyl-7-oxo-lH,3H,7H-pyrido-[3,2,1-i,j][3,1]bel~zu~zille-6-carboxylic
1 5 acid
9,10-difluoro-3-dimethyl-7-oxo-lH,3H,7H-pyrido-[3,2,1-i.j][3,1]benzoxazine-
6-carboxylic acid
ethyl 9,10-difluoro-3-methyl-7-oxo-lH,3H,7H-pyrido-[3,2,1-i,j][3,1]benzoxazine-
6-carboxylate
The amines of the formula (III) which are used as starting compounds are known.
Chiral amines can be employed in the form of the racemates as well as
enantiomerically or diastereomerically pure compounds.
Examples which may be mentioned are:
2,7-diazabicyclo[3 .3 .O]octane
2-methyl-2,7-diazabicyclo[3.3.0]octane
2,8-diazabicyclo[4.3 .O]nonane
- 18 -
21 94~
.
-
2-methyl-2,8-diazabicyclo[4.3 .O]nonane
2-oxa-5,8-diazabicyclo[4.3 .O]nonane
S-methyl-2-oxa-5,8-diazabicyclo[4.3 .O]nonane
2-amino-8-azabicyclo[4.3 .O]non-3-ene
2-methylamino-8-azabicyclo[4.3.0]non-3-ene
4-methyl-2-methylamino-8-azabicyclo[4.3 .O]non-3 -ene
S-methyl-2-methylamino-8-azabicyclo[4.3 .O]non-3 -ene
2-dimethylamino-8-azabicyclo[4.3 .O]non-3 -ene
2-ethylamino-8-azabicyclo[4.3 .O]non-3 -ene
2-methylaminomethyl-8-azabicyclo[4.3.0]non-3-ene
2-hydroxy-8-azabicyclo[4.3 .O]non-3 -ene
S -isopropyl-2-methylamino-8-azabicyclo[4.3 .O]non-3 -ene
2-amino-5-isopropyl-8-azabicyclo[4.3 .O]non-3 -ene
2-amino-5-methyl-8-azabicyclo[4.3 .O]non-3-ene
2-hydroxymethyl-8-azabicyclo[4.3.0]non-3-ene
2-amino-5 -cyclopropyl-8-azabicyclo[4.3 .O]non-3 -ene
8-azabicyclo[4.3 .O]non-2-ene
~ ethyl 8-azabicyclo[4.3.0]non-4-ene-2-carboxylate
2-hydroxymethyl-8-azabicyclo[4.3 .O]non-4-ene
2-amino-8-azabicyclo[4.3.0]non-4-ene
2-ethyloxycarbonylamino-8-azabicyclo[4.3 .O]non-4-ene
2-tert-butyloxycarbonylamino-8-azabicyclo[4.3 .O]non-4-ene
2-benzyloxycarbonylamino-8-azabicyclo[4.3 .O]non-4-ene
2-allyloxycarbonylaminomethyl-8-azabicyclo[4.3 .O]non-4-ene
2-aminomethyl-8-azabicyclo[4.3.0]non-4-ene
2-ethyloxycarbonylaminomethyl-8-azabicyclo[4.3.0]non-4-ene
2-tert-butyloxycarbonylaminomethyl-8-azabicyclo[4.3 .O]non-4-ene
2-methylamino-8-azabicyclo[4.3 .O]non-4-ene
2-ethylamino-8-azabicyclo[4.3 .O]non-4-ene
2-cyclopropylamino-8-azabicyclo[4.3.0]non-4-ene
2-dimethylamino-8-azabicyclo[4.3 .O]non-4-ene
2-[(2-hydroxyethyl)-amino]-8-azabicyclo[4.3 .O]non-4-ene
2-amino- 1 -methyl-8-azabicyclo[4.3 .O]non-4-ene
2-amino-2-methyl-8-azabicyclo[4.3 .O]non-4-ene
2-amino-3-methyl-8-azabicyclo[4.3.0]non-4-ene
2-ethyloxycarbonylamino-3 -methyl-8-azabicyclo[4.3 .O]non-4-ene
2-tert-butyloxycarbonylamino-3 -methyl-8-azabicyclo[4.3 .O]non-4-ene
- 19 -
~ 94~4
-
2-benzyloxycarbonylamino-3 -methyl-8-azabicyclo[4.3 .0]non-4-ene
2-allyloxycarbonylaminomethyl-3 -methyl-8-azabicyclo[4.3 .0]non-4-ene
2-amino-4-methyl-8-azabicyclo[4.3 .0]non-4-ene
2-amino-5-methyl-8-azabicyclo[4.3 .0]non-4-ene
2-amino-6-methyl-8-azabicyclo[4.3.0]non-4-ene
2-amino-7-methyl-8-azabicyclo[4.3 .0]non-4-ene
2-amino-9-methyl-8 -azabicyclo[4.3 .0]non-4-ene
The substituted 8-azabicyclo[4.3.0]non-4-enes and 8-azabicyclo[4.3.0]non-2-enes as
well as their preparation are disclosed in DE-OS (German Published Specification)
4 230 804.
They are obtained by reacting suitable dienes with suitable dienophiles in a Diels-
Alder reaction, which can be carried out interrnolecularly or intramolecularly, and,
if appropriate, subsequently carrying out further chemical reactions so as to construct
the pyrrolidine ring, if appropriate, and to introduce substituents which are desired
15 for their biological action and, as the last step, ~limin~ting the protective group from
the pyrrolidine nitrogen.
If the Diels-Alder reaction is carried out intramolecularly, compounds of the formula
(1) or (2)
N-P ~
R8lR9 R8 R9 R8,R9 R R9
20 in which
R8 and R9 have the abovementioned meaning and
P represents a protective group (for example allyl, acyl, carbarnoyl or
trityl), and
Z represents hydrogen, a carboxyl, carboxylate or carboxamide group, CN
or NO~,
- 20 -
~ . ... . ~ .. !
,, .
~ 1 ~4694
-
are reacted to give compounds of the formula (3) [starting from (1)] or (4) [starting
from (2)]
Z Z
R V~--,N-P (3~, R ~~
in which
5 R8, R9, P and Z have the abovementioned mç~nings
Some intramolecular Diels-Alder reactions of a similar type are known: J.M. Mellor,
A.M. Wagland; J. Chem. Soc. Perkin I, 997-1005 (1989); W.R. Roush, S.E. Hall;
J. Am. Chem. Soc. 103, 5200 (1980); E. Ciganek; Organic Reactions 32, 1-374
(1984). However, these publications fail to mention protective groups which are not
10 only suitable for the reaction but can also be elimin~ted subsequently without
problems.
If the Diels-Alder reaction is carried out intermolecularly, dienes of the formula (5)
are reacted with dienophiles of the formula (6) to give compounds of the formula (7),
and, if appropriate after modification of groups Zl and Z2, for example conversion
15 of a cyclic carboxylic anhydride into a diester with ~.limin~tion of the protective
groups pl or pl and p2, subjected to a cyclization reaction to give the lactams of the
formula (8).
.
.
21 946q4
-
~ Z1
R8,R9--~ ~ 8 9 ~--
P' (5) R~R ... 2 (6)
p2
R8,R9~ XZ2 ~rZ Rll,R9--~N-H
P2-N ~ (8)
In formula (5), (6), (7) and (8), R8 and R9 have the abovementioned meaning,
pl represents an acyl or carbamoyl protective group if
p2 represents hydrogen, or
pl together with p2 forms an imide,
zl and Z2 represent hydrogen, carboxyl, carboxylate or carboxamide groups, CN
or NO2, where at least one of the two groups zl or Z2 must be a
carboxylate group or a carboxamide group or CN, or zl and Z2
~ together form a bridge, so that a cyclic carboxylic anhydride is formed.
10 Preferred protective groups P, pl and p2 are those protective groups in which, under
the conditions used for their elimin~tion, cyclization to the lactam and, if appropriate,
an esterification of a second, as yet free carboxyl function with the alcohol used as
the solvent takes place, in such a manner that all reaction steps can be carried out in
a one-pot reaction and that uncontrolled conversion of starting substances, if
15 appropriate diastereomerically and enantiomerically pure starting substances, into
isomer mixtures which cannot be separated, or are difficult to separate, does not take
place.
- 22 -
~ 1 94694
Examples which may be mentioned are:
1. the tert-butyloxycarbonyl protective group
(~limin~ted using aqueous or alcoholic acids)
2. the phth~limido protective group
(aminolysis using primary amines in aqueous or anhydrous alcohols as solvent)
The reaction of the compounds of the formula (II) with compounds of the formula
(III), in which the compounds (III) may also be employed in the form of their salts,
such as, for example, the hydrochlorides, is preferably carried out in a diluent such
as dimethyl sulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, hexamethyl-
phosphoric triamide, sulpholane, acetonitrile, water, an alcohol such as methanol,
ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Mixtures of
these diluents can also be used.
Acid binders which can be used are all customary inorganic and organic acid-binding
agents. These preferably include the alkali metal hydroxides, alkali metal carbonates,
organic amines and amidines. Substances which may be mentioned specifically as
being particularly suitable are: triethylamine, 1,4-diazabicyclo[2.2.2]octane
(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine (III).
The reaction temperatures can be varied within a substantial range. In general, the
process is carried out between approximately 20 and 200~C, preferably between 80and 180~C.
The reaction can be carried out under atrnospheric pressure, but also under elevated
pressure. In general, the process is carried out at pressures of between 1 bar and
100 bar, preferably between 1 and 10 bar.
When carrying out the process according to the invention, 1 to 15 mol, preferably 1
25 to 6 mol, of the compound (III) are employed per mole of the compound (II).
During the reaction, free amino groups may be protected by a suitable amino
protective group, for example by the tert-butoxycarbonyl radical, and, after thereaction has ended, set free again by treatment with a suitable acid such as
hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, Methoden der
2 1 94694
Organischen Chemie [Methods in Organic Chemistry], Volume E4, page 144 (1983);
J.F.W. Mc Omie, Protective Groups in Organic Chemistry (1973), page 43).
The esters according to the invention are obtained by reacting an alkali metal salt of
the basic carboxylic acid which can optionally be protected on the N atom by a
S prote~ e group, such as the tert-butoxycarbonyl radical, with suitable halogenoalkyl
derivatives in a solvent such as dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, dimethyl sulphoxide or tetramethylurea, at temperatures from
approximately 0 to 100~C, preferably 0 to 50~C.
The acid addition salts of the compounds according to the invention are prepared in
10 the custom~ry manner, for example by dissolving the betaine in a sufficient amount
of aqueous acid and precipitating the salt with an organic solvent which is miscible
with water, such as methanol, ethanol, acetone or acelonillile. It is also possible to
heat equivalent amounts of betaine and acid in water or an alcohol such as glycol
monoethyl ether and subsequently evaporating the solution to dryness or filtering off
15 with suction the salt which has precipitated. Pharrn~ce~ltically utilizable salts are to
be understood as meaning, for example, the salts of hydrochloric acid, sulphuric acid,
acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid,
methanesulphonic acid, 4-toluenesulphonic acid, galacturonic acid, gluconic acid,
embonic acid, glutamic acid or aspartic acid. The compounds according to the
20 invention may furthermore be bound to acidic or basic ion exchangers.
The alkali metal salts or alkaline earth metal salts of the carboxylic acids according
to the invention are obtained, for example, by dissolving the betaine in a
substoichiometric amount of alkali metal hydroxide solution or alkaline earth metal
hydroxide solution, filtering off undissolved betaine and evaporating the filtrate to
25 dryness. Pharmaceutically suitable are sodium salts, potassium salts or calcium salts.
The corresponding silver salts are obtained by reacting an alkali metal salt or
alkaline earth metal salt with a suitable silver salt, such as silver nitrate.
The compounds according to the invention have a powerful antibiotic action and
combine low toxicity with a broad antibacterial spectrum against Gram-positive and
30 Gram-negative microorg~ni~m~ in particular also against those which are resistant to
various antibiotics such as, for example, penicillins, cephalosporins, aminoglycosides,
sulphonamides and tetracyclins.
- 24 -
- .
21 94694
These valuable properties allow them to be used as chemotherapeutic action in
medicine and veterinary medicine as well as substances for preserving inorganic and
organic materials, in particular a wide range of organic materials, for example
polymers, lubricants, paints, fibres, leather, paper and wood, foodstuffs and water.
5 The compounds according to the invention are active against a very broad spectrum
of microor~ni~m.~ With their aid, Gram-negative and Gram-positive bacteria and
bacteria-like microorg~ni~m~ can be controlled, and the diseases caused by thesepathogens can be prevented, alleviated and/or cured.
The compounds according to the invention are distin~ hed by an improved activity10 against dormant and resistant microorg~ni.~m~. In the case of dormant bacteria, that
is to say bacteria which show no detectable growth, the compounds are active at
concentrations which are below those of similar substances. This not only refers to
the amount to be employed, but also to the speed of destruction. Such results were
observed in Gram-positive and -negative bacteria, in particular in Staphylococcus
15 aureus, Micrococcus luteus and Enterococcus faecalis.
The compounds according to the invention also show surprising, increased activity
against bacteria which are classified as less sensitive to comparable substances, in
particular resistant Staphylococcus aureus and Enterococcus faecalis.
The compounds according to the invention are particularly active against bacteria and
20 bacteria-like microorg~ni~m~. They are therefore particularly suitable for the
prophylaxis and chemotherapy of local and systemic infections in human and
veterinary medicine which are caused by these pathogens.
The compounds are furthermore suitable for controlling protozoonoses and
helminthoses.
25 The compounds according to the invention can be used in various pharmaceutical
preparations. Preferred pharmaceutical preparations which may be mentioned are
tablets, coated tablets, capsules, pills, granules, suppositories, injectable solutions,
suspensions and emulsions, solutions, suspensions and emulsions for oral
administration, furthermore pastes, ointments, gels, creams, lotions, powders and
30 sprays.
- 25 -
2 1 94694
The minimllm inhibitory concentrations (MICs) were determined by serial dilutionmethods using Iso-Sensitest agar (Oxoid). For each test substance, a series of agar
plates was prepared whose active compound concentrations decreased as the dilution
was doubled. The agar plates were inoculated using a multipoint inoculator (Denley).
5 The cultures used for inoculation were overnight cultures of the pathogen which had
previously been diluted to such an extent that each inoculation point contained
approximately 104 colony-forming units. The inoculated agar plates were incubated
at 37~C, and the microbial growth was read off after approximately 20 hours. TheMIC value (,ug/ml) indicates the lowest active compound concentration at which no
10 growth was observed with the naked eye.
The following table lists the MIC values of some of the compounds according to the
invention in comparison with 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-
lH,3H,7H-pyrido[3,2,1-iJ]-[3,1]-benzoxazine-6-carboxylic acid (EP-O 373 531) as
reference compound.
- 2G -
-
21 946q4
-
Table: MIC values
Species Strain Exarnple No. Reference
4 5
E. coli Z 431 Lit 0.015 0.06 <0.015 0.05
21 Bui 4 4 4 0.05
Klebsiella
pneumoniae 2363 Ge 0.06 0.12 0.12 0.5
Salmonella 1 Fr 0.06 0.25 0.12
Enterobacter 0,4 Ge 02-33 0.25 0.12 0.12
Staphylococcus Z 2 Lit 0.12 0.5 0.12 16
aureus 3781 Ge 0.12 8 0.12 128
Pseudomonas BS 698 TGD 4 8 16 64
21 94694
Example 1
o o
~OH
H2N~N~N
10-(2-Amino-8-azabicyclo[4,3,0]non-3-en-8-yl)-9-fluoro-3-methyl-7-oxo-
1II,311,7~-pyrido-[3,2,1-i,J][3,1]benzoxazine-6-carboxylic acid
293 mg (1.04 mmol) of 9,10-difluoro-3-methyl-7-oxo-lH,3H,7H-pyrrido-
[3,2,1-i,i][3,1]benzoxazine-6-carboxylic acid together with 200 mg (1.30 mmol) of
2-amino-8-azabicyclo[4,3,0]non-3-ene and 156 mg (1.4 mmol) of 1,4-diazabicyclo-
[2,2,2]octane are heated in 1.5 ml of dimethyl sulphoxide for 60 minlltes at 130~C
under argon. After cooling, the mixture is poured into water, the pH is brought to 7.5
using dilute hydrochloric acid, and the product is filtered off with suction. It is
washed with water and dried in the air. For purification, the product is recryst~ ed
from ethanol.
Yield: 150 mg (36% of theory)
Melting point: 207~C (decomposition)
15 Diastereomer mixture
The following are obtained analogously
- 28 -
2 1 94~94
Examnle 2
o O
~OH
HO-H2C ~ o~
10-(2-Hydroxymethyl-8-azabicyclo[4,3,0]non-3-en-8-yl)-9-fluoro-3-methyl-7-oxo-
lH,3H,7H-pyrido-[3,2,1-i,j][3,1]benzoxazine-6-carboxylic acid
5 Melting point: 230~C (decomposition)
Diastereomer mixture
Exam~le 3
O o
OH
~ ~OJ~
10-(2-Amino-5-isopropyl-8-azabicyclo[4,3,0]non-3-en-8-yl)-9-fluoro-3-methyl-
7-oxo-1H,3H,7H-pyrido-[3,2,1-i,j] [3,1]benzoxazine-6-carboylic acid
Melting point: 150~C (decomposition)
Diastereomer mixture
- 29 -
2 1 94~4
Example 4
O O
~N ~OH
10-(2.8-Diazabicyclo[4,3,01nonan-8-yl)-9-fluoro-3-methyl-7-oxo-lEI,3EI,7EI-pyrido-
[3,2,1-i,j][3,1]benzoxazine-6-carboxylic acid
5 Melting point: 1 85~C (decomposition)
Diastereomer mixture
~xample S
O o
~OH
~,
9-Fluoro-3-methyl-10-(2-methylamino-8-azabicyclo[4.3.0]non-3-en-8-yl)-7-oxo-
1El,3~,7H-pyrido[3,2,1-i,j][3,1]benzoxazine-6-carboxylic acid
Melting point: 200~C (decomposition)
Diastereomer mixture
- 30 -
2 1 94694
_,
Example 6
H o O
F~ OH
H ol
9-Fluoro-3 -methyl- 1 0-(2-methylamino-8-azabicyclo[4.3 .0]non-4-en-8yl)-7-oxo-
lH,3H,7H-pyrido[3.2.1-ij] [3.1] benzoxacine-6-carboxylic acid
5 Melting point: 290~C (decomposition)
Diastereomer mixture.
Preparation of the intermediates:
Example A:
8-Azabicyclo r4.3.01 non-2-ene
A.1. (1~)-1-Bromo-2,4-Pentadiene
~ ~Br
At 0~C, introduce 84 g (1.0 mol) of 1,4-pentadien-3-ol. Add dropwise with stirring
150 ml (# 1.3 mol) of 48% strength aqueous hydrobromic acid in such a manner that
the intern~l temperature does not rise above 5~C. When the addition is complete,15 continue stirring for 1 h at room temperature. The organic phase is separated off and
reacted further without purification.
Yield: 107-129 g (73-88% of theory)
21 94694
_.
A.2. (E)-1-(2-ProPenvlamino)-2,4-Pentadiene
~N/\~
H
Introduce 228 g (4.0 mol) of 1-amino-2-propene. Add dropwise with stirring 58.8 g
(0.4 mol) of (E)- l-bromo-2,4-pentadiene (title compound of Example A. l .). Keep the
5 internal temperature in a range of 20-30~C by means of cooling. Stir for 5 h at room
temperature. ConcenL~te batch at 150 mbar. Add 20 g (0.5 mol) of sodium
hydroxide, dissolved in 200 ml of water, extract the mixture twice using in each case
100 ml of methylene chloride, dry using sodium sulphate, add 0.1 g of
4-Lydlw~y~1isole, conce~ ate and distil at 40 mbar. 10-20 ppm of 4-hydlo~y~isole10 are added to stabilize the distillate.
Yield: 33-35 g (67-72% of theory)
Boiling point: - 77-82~C at 40 mbar
IH NMR (CDCl3): o = 6.07-6.48 (m, 2H); 5.64-6.07 (m, 2H); 5.00-5.27 (m, 4H);
3.19-3.36 ppm (m, 4H).
15 A.3. N-r(E)-2~4-Pentadienyll-N-(2-propenyl)-acetamide
NJ~cH3
Introduce 24.6 g (0.2 mol) of (E)-1-(2-propenylamino)-2,4-pentadiene (title
compound of Example A.2.), dropwise add 22.4 g of acetic anhydride, and stir
overnight at room temperature. Concentrate and react further in the form of the crude
20 product.
- 32 -
2 1 94694
-
A.4. 8-Acet~1-8-azabicyclo~4.3.01non-2-ene
H
Dissolve 33.1 g (0.2 mol) of N-[(E)-2,4-pentadienyl]-N-(2-propenyl)-acetamide (title
compound of Example A.3.) in 200 ml of xylene, pass through a vigorous stream of5 nitrogen for 15 min, add 0.1 g of 4-hydroxyanisole, then reflux overnight.
Concentrate and distil under a high vacuum.
Yield: 23.1 g (70% of theory based on the title compound of Example A.2.)
Boiling point: 88-93~C at 0.05 mbar
A. 5.8-Azabicvclol4.3.01non-2-ene
~N~CH,
Reflux 16.5 g (0.1 mol) of 8-acetyl-8-azabicyclo[4.3.0]non-2-ene (title compound of
Example A.4.) for 3 h in a mixture of 100 ml of 45% strength sodium hydroxide
solution, 50 ml of water and 100 ml of 1,2-ethanediol. After cooling, extract four
times using in each case 50 ml of diethyl ether. Dry combined organic phases using
15 sodium sulphate and distil under a high vacuum.
Yield: 6.6 g (54% of theory)
Boiling point: 36-44~C at 0.35 mbar
IH NMR (CDCl3): ~ = 5.79 (m, lH); 5.74 (m, lH); 3.02-3.17 (m, 2H); 2.47-2.72 (m,2H); 2.06-2.30 (m, 2H); 1.91-2.06 (m, 2H); 1.68 (m, lH); 1.45 ppm (m, lH).
